The objective of the proposed research is to discover the neural mechanism(s) involved in osteoporosis following spinal cord injury. The results of these studies may be useful in understanding the mechanisms in osteoporosis of other etiologies (e.g., immobilization, post-menopausal osteoporosis, etc.). This research, using an animal model of spinal cord injury with some characteristics common to many spinal cord injured patients, represents a feasible way of investigating the causes of osteoporosis and for later developing possible treatments to prevent or replace this bone loss. The proposed research will determine if there are changes in neuropeptides, neurotransmitters and cytokines in nerves supplying bone and in their receptors on bone cells. Since both the central and peripheral nervous systems are altered after spinal trauma, we hypothesize that changes in these substances in nerves are involved in the osteoporosis which develops following spinal cord injury. This hypothesis can not be fully tested until we have fully characterized the osteoporosis and changes in neural factors after injury in this animal model. Therefore, the specific aims of this proposal are to: l. Define the alterations in bone metabolism and structure that occur following spinal cord injury (Phase 1); 2. Determine what, if any, changes in neural factors in nerve fibers supplying bone and periosteum occur following spinal cord injury (Phase 11); 3. Determine what, if any, changes in receptors for these neural factors occur in osteogenic tissue (Phase III); 4. Correlate the changes in neural factors and their receptors with changes in bone metabolism over time. Histomorphometry, mechanical testing, radioimmunoassays and molecular biology will be used to characterize bone loss over time following spinal cord injury (Phase I). In Phase II we will use immunohistochemistry, radioimmunoassays and molecular biology to determine changes in neuropeptide and catecholamine distribution and levels in bone and periosteum over time following spinal cord injury. Specifically, we will focus on two sensory neuropeptides [calcitonin gene-related peptide and substance P], two sympathetic neuropeptides [vasoactive intestinal polypeptide and neuropeptide Y), norepinephrine, and the cytokine interleukin-1. These substances are known to be contained in nerve fibers in bone and have been implicated as modulators of bone metabolism in vitro. Immunohistochemistry, homogenate receptor binding assays, and autoradiographic methods will be used to evaluate receptor changes (Phase III). The correlation of bone and nerve changes following spinal cord injury will provide a clearer understanding of the mechanisms underlying the development of osteoporosis following spinal cord injury. It will also provide a basis for future studies on the effects of specific neural factors on the development of osteoporosis using other in vivo techniques (e.g immunoneutralization and infusion.)